The once-weekly, oral proteasome inhibitor that Takeda Pharmaceutical Co. Ltd., with its Millennium oncology unit, hopes will eventually replace Velcade (bortezomib), which loses patent protection later this decade, entered a Phase III trial in newly diagnosed multiple myeloma (MM).

Called TOURMALINE-MM2, the study will enroll about 700 patients and compare MLN9708 plus Revlimid (lenalidomide, Celgene Corp.) and dexamethasone to placebo plus lenalidomide and dexamethasone in patients with MM who are not candidates for transplant. The primary endpoint is progression-free survival (PFS), with key secondary endpoints including safety, rate of complete response (CR), pain response and overall survival (OS).

At December's American Society of Hematology (ASH) meeting, Phase I/II data showed the combination therapy achieved a CR in two patients, and one reached a very good partial response. Wells Fargo analyst Brian Abrahams wrote in a research report at the time that MLN9708 "continues to appear potentially complementary, but unlikely a competitive threat to Celgene," of Summit, N.J.

Overall response rate (ORR) stayed high – 90 percent – but CR only improved moderately, which did "not indicate profound deepening of responses over time," Abrahams wrote. "Though tested on an older, likely more difficult-to-treat population, this was not nearly as impressive as the presented CR/near CR rate for proteasome inhibitor carfilzomib in a similar regimen with Revlimid-dexamethasone, which reached 75 percent by eight cycles. Peripheral neuropathy with MLN9708 looked manageable, though Grade III/IV rash of 18 percent may be meaningful."

The MM therapy carfilzomib, branded Kyprolis, from Onyx Pharmaceuticals Inc., of South San Francisco, is expected to sell as much as $897 million in 2017, which is also, coincidentally, the year Velcade loses patent protection. Takeda expects top-line data from the Phase III trial with MLN9708 in late 2018.

"The study includes a planned follow-up of up to five years," Dixie Esseltine, vice president of global clinical development for Takeda, told BioWorld Today, adding that MLN9708 is differentiated from competitors in three ways. As the first oral proteasome inhibitor to reach Phase III trials, the drug could offer convenience not previously seen in MM therapies. Broad preclinical activity has been found with MLN9708 against hematological malignancies and solid tumors, she said, though no clinical experience with solid tumors exists. As for safety, no severe (i.e., greater than Grade III) peripheral neuropathy (PN) was seen at or below the maximum tolerated dose, with one case of Grade III PN turning up at a dose that was almost twice the recommended Phase II dose. Tolerability, Esseltine said, is "encouraging."

Regarding Onyx's Kyprolis, she said, "It's inappropriate to try to compare early stage results to other treatments." The rash cited in ASH data "appears to be manageable, and no patients have discontinued" as a result of it, Esseltine said. "We expect the ultimate use to [of MLN9708] be in combination, initially with Revlimid," as studied in the Phase III trial. As new agents emerge, the compound will be studied in those combinations, she said.

In February, the FDA approved Celgene's second-generation Revlimid, called Pomalyst (pomalidomide), to treat patients with MM whose disease progressed after being treated with other cancer drugs. (See BioWorld Today, Feb. 11, 2013.)

Decision Resources, in a report disclosed this month, expressed thought leaders' optimism for Onyx's Phase III ASPIRE trial, testing Kyprolis in combination with Revlimid and low-dose dexamethasone vs. Revlimid and dexamethasone alone in relapsed MM patients who have received one to three prior therapies. That trial is being carried out under a special protocol assessment with the FDA.

The report, titled "As Carfilzomib and Pomalidomide Make Inroads Into the Market, What Key Attributes Will Differentiate Emerging Therapies According to Hematological Oncologists and Payers?," found that U.S. managed care organization pharmacy directors are demanding that new therapies provide significant improvements in OS over premium-priced Revlimid. Half of surveyed payers would not reimburse a new therapy priced the same as Revlimid or higher that offers a three-month improvement in OS over Revlimid.

The MM space remains busy with contenders trying approaches that seem to hold promise, though disappointments have been evident, too. In March, Aeterna Zentaris Inc., of Quebec City, heard from a data safety monitoring board that the Phase III study testing PI3/Akt inhibitor perifosine in MM probably would miss its endpoints. Perifosine earlier had failed to improve OS in colorectal cancer, an outcome that led to the end of Aeterna's 2002 partnership with New York-based Keryx Biopharmaceuticals Inc. (See BioWorld Today, March 12, 2013, and April 3, 2012.)

Another hopeful: Array BioPharma Inc., of Boulder, Colo. At the 2012 ASH meeting, the company unveiled Phase II data with ARRY-520, a kinesin spindle protein inhibitor, showing that patients with triple-refractory MM and a median number of 10 prior treatment regimens came up with a 22 percent ORR when given ARRY-520 plus low-dose dexamethasone.